Rho, a low molecular weight GTP-binding protein, is activated by signals from various cell membrane receptors. The activated Rho functions, via Rho kinase signal transduction pathway and actomyosin signal transduction pathway, as a molecular switch for various cellular phenomena such as contraction of smooth muscles, morphological changes in cells, cell movement, cell division, intercellular adhesion, platelet aggregation, leukocyte aggregation, and infiltration and increase of cancer cells.
It has also been known that such cellular phenomena deeply participate in diseases such as hypertension, angina pectoris, asthma, peripheral circular disorder, premature delivery, arteriosclerosis, cancer, inflammatory diseases, autoimmune diseases, AIDS, fertilization and implantation of a fertilized egg, osteoporosis, brain dysfunction, gastrointestinal dysfunction by bacteria, glaucoma and retinopathy.
Accordingly, it is believed that, when Rho is inhibited, prevention and/or treatment of the above-mentioned diseases associated with Rho are/is possible.
On the other hand, it has also been known that, when Rho kinase, which is present in the downstream of signal transduction pathway mediated by Rho, is inhibited, various cellular phenomena caused by Rho can be suppressed.
That is, compounds which inhibit the Rho kinase are believed to be effective preventive and/or therapeutic agent(s) for the above-mentioned diseases associated with Rho such as hypertension, angina pectoris, asthma, peripheral circular disorder, premature delivery, arteriosclerosis, cancer, inflammatory diseases, autoimmune diseases, AIDS, fertilization and implantation of a fertilized egg, osteoporosis, brain dysfunction, gastrointestinal dysfunction by bacteria, glaucoma and retinopathy (WO 98/06433).
A Rho kinase inhibitor is generally defined as an inhibitor of serine/threonine kinase activated as a result of activation of Rho. The Rho kinase inhibitor includes compounds which inhibit ROKA (ROCK-II) or ROKβ (ROCK-I, p160ROCK) and other compounds which inhibit proteins having a serine/threonine kinase activity.
Examples of the known Rho kinase inhibitor include amide derivatives disclosed in WO 98/06433; isoquinoline sulfonyl derivatives disclosed in WO 97/23222, Nature, 389, 990-994 (1997) and WO 99/64011; heterocyclic amino derivatives disclosed in WO 2001/56988; indazole derivatives disclosed in WO 2002/100833 and WO 2005/035506; and quinazoline derivatives disclosed in WO 2002/076976 and WO 2002/076977.
It has also been disclosed in Patent WO 2005/035506, WO 2000/09162 and WO 2000/57914 that a Rho kinase inhibitor is useful as a therapeutic agent for glaucoma.
However, in any of the above-mentioned documents, there is no specific disclosure for the indazole derivative having a spiro ring structure in a side chain according to the present invention.